Department of Pharmacology and Pharmacology PhD Program, Weill Cornell Medicine, New York, New York, United States of America.
PLoS One. 2020 Dec 15;15(12):e0243842. doi: 10.1371/journal.pone.0243842. eCollection 2020.
Activation of the aryl hydrocarbon receptor (AHR) by the environmental toxin dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) causes diverse toxicities, including thymus atrophy and hepatosteatosis. The mechanisms by which AHR activation by TCDD leads to these toxicities are not fully understood. Here we studied the effects of TCDD on a major energy pathway, glycolysis, using the chick embryo close to hatching, a well-established model for studying dioxin toxicity. We showed that 24 hr of TCDD treatment causes changes in glycolysis in both thymus and liver. In thymus glands, TCDD decreased mRNAs for glycolytic genes and glucose transporters, glycolytic indices and levels of IL7 mRNA, phosphorylated AKT (pAKT) and HIF1A, stimulators of glycolysis and promoters of survival and proliferation of thymic lymphocytes. In contrast, in liver, TCDD increased mRNA levels for glycolytic genes and glucose transporters, glycolytic endpoints and pAKT levels. Similarly, increases by TCDD in mRNA levels for glycolytic genes and glucose transporters in human primary hepatocytes showed that effects in chick embryo liver pertain also to human cells. Treatment with the glycolytic inhibitor 2-deoxy-d-glucose exacerbated the effects on thymus atrophy by TCDD, supporting a role for decreased glycolysis in thymus atrophy by TCDD, but did not prevent hepatosteatosis. NAD+ precursors abolished TCDD effects on glycolytic endpoints in both thymus and liver. In summary, we report here that dioxin disrupts glycolysis mediated energy metabolism in both thymus and liver, and that it does so in opposite ways, decreasing it in the thymus and increasing it in the liver. Further, the findings support NAD+ boosting as a strategy against metabolic effects of environmental pollutants such as dioxins.
芳香烃受体 (AHR) 的激活由环境毒素二恶英 (2,3,7,8-四氯二苯并对二恶英, TCDD) 引起，导致多种毒性，包括胸腺萎缩和肝脂肪变性。TCDD 激活 AHR 导致这些毒性的机制尚未完全了解。在这里，我们使用接近孵化的鸡胚研究了 TCDD 对主要能量途径糖酵解的影响，这是研究二恶英毒性的成熟模型。我们表明，24 小时的 TCDD 处理导致胸腺和肝脏中的糖酵解发生变化。在胸腺中，TCDD 降低了糖酵解基因和葡萄糖转运蛋白、糖酵解指数和 IL7 mRNA、磷酸化 AKT(pAKT) 和 HIF1A 的 mRNA 水平，这些物质是糖酵解的刺激物，也是胸腺淋巴细胞存活和增殖的促进剂。相比之下，在肝脏中，TCDD 增加了糖酵解基因和葡萄糖转运蛋白、糖酵解终点和 pAKT 水平的 mRNA 水平。同样，TCDD 增加人原代肝细胞中糖酵解基因和葡萄糖转运蛋白的 mRNA 水平表明，鸡胚肝脏中的效应也适用于人类细胞。糖酵解抑制剂 2-脱氧-d-葡萄糖的处理加剧了 TCDD 对胸腺萎缩的影响，支持 TCDD 引起的胸腺萎缩中糖酵解减少的作用，但不能预防肝脂肪变性。NAD+前体消除了 TCDD 对胸腺和肝脏糖酵解终点的影响。总之，我们在这里报告说，二恶英破坏了胸腺和肝脏中糖酵解介导的能量代谢，并且以相反的方式破坏了它，在胸腺中减少了它，在肝脏中增加了它。此外，这些发现支持 NAD+ 增强作为对抗环境污染物如二恶英代谢影响的策略。
